Production of the novel lipopeptide antibiotic trifluorosurfactin via precursor-directed biosynthesis

Incorporation of fluorine into antibiotics can moderate their biological activity, lipophilicity and metabolic stability. The introduction of fluorine into an antimicrobial lipopeptide produced by Bacillus sp. CS93 via precursor-directed biosynthesis is described. The lipopeptide surfactin is synthesised non-ribosomally by various Bacillus species and is known for its biological activity. Administering 4,4,4-trifluoro-dl-valine to cultures of Bacillus sp. CS93 results in the formation of trifluorosurfactin in quantities sufficient for detection by LC–MS/MS. 19F NMR analysis of the culture supernatant revealed that the bulk of the fluorinated amino acid was transformed and thus was unavailable for incorporation into surfactin. Detection of ammonia, and MS analysis indicated that the transformation proceeds with deamination and reduction of the keto acid, yielding 4,4,4-trifluoro-2-hydroxy-3-methylbutanoic acid.

Almost one quarter of drugs contain fluorine, although incorporating fluorine into complex natural products synthetically is challenging. Precursor-directed biosynthesis is an alternative method of generating fluorinated natural products and here we demonstrate that Bacillus sp. CS93 produces the trifluorinated derivative of surfactin when cultured in the presence of 4,4,4-trifluoro-dl-valine.Figure optionsDownload as PowerPoint slideHighlights
► Employed precursor-directed biosynthesis to biosynthesise fluorinated lipopeptides.
► Bacillus sp. CS93 produced small quantities of trifluorosurfactin when incubated with 4,4,4-trifluoro-dl-valine.
► Most of the fluorinated amino acid was converted to 4,4,4-trifluoro-2-hydroxy-3-methylbutanoic acid.